The p21 activated kinase-1 (Pak1) belongs to a family of serine/threonine protein kinases directly activated by small GTPases, Cdc42 and Rac1. Pak1 is abundant in the heart and localizes to cell and nuclear membranes, intercalated discs and to Z-discs in ventricular myocytes. The active form of Pak1 in cardiomyocytes increases Ca2+ sensitivity of myofilament force development through activation of PP2A (Ke 2004, p 194-200) and in SA nodal cells, Pak1 inhibits isoproterenol-stimulated activation of L-type Ca2+ channel and delayed rectifier potassium channels (Ke 2007, p 1317-1327). Other studies have shown that in endothelial cells, Pak1 activation induces dephosphorylation of myosin regulatory light chain and inhibition of thrombin-induced barrier dysfunction (Ke 2007, p 281-288) and in HeLa cells, expression of constitutively active Pak1 induces loss of stress fibers and dissolution of focal adhesion complexes (Manser 1997, p 1129-1143). These studies suggest a role of Pak1 in cytoskeletal function and reorganization. In transgenic mice expressing an active Rac1 in the heart, hypertrophy developed followed by dilated cardiomyopathy with altered intracellular partitioning of Pak1 in the ventricle myocytes (Sussman 2000, p 875-886).
A prominent post-translational modification of Pak1 is autophosphorylation, which is correlated with its activity (Manser 1997, p 1129-1143; Zhao 1998, p 2153-2163). Pak1 is autophosphorylated at seven serine/threonine sites most of which occur at the N-terminal half of the kinase. Substitution of threonine 423, the last autophosphorylation site, with glutamic acid renders the kinase constitutively active (Manser 1997, p 1129-1143). Although there is abundant expression of Pak1 in cardiomyocytes, smooth muscle and endothelial cells, the function of Pak1 in the cardiovascular system remains poorly understood (Sheehan 2007, p 963-973). Moreover, potential modifications in autophosphorylation of native Pak1 in failing heart and in other pathological conditions have not been defined.
Studies in skeletal muscle have shown that Pak1 activity was responsive to insulin treatment (Tsakiridis 1996, p 19664-19667) suggesting that Paks are also phosphorylated by tyrosine kinase (Bagheri-Yarmand 2001, p 29403-29409; He 2004, p 96-101; Yang 2004, p 658-667). Tyrosine phosphorylation of Pak1 may also play an important role in regulation of cardiac function.